Deterioration of the intervertebral disks, located between each vertebra, is common in older vertebrates. Age-related changes in the intervertebral disks are thought to cause most cases of back pain. Back pain affects nearly everyone at some point of their lives, with 1.5 million people a year becoming disabled. The center region of the intervertebral disk is composed of soft, highly hydrated tissue called the nucleus pulposus. Dehydration or damage to the nucleus pulposus can result in inefficient transfer of load between the intervertebral disks, leading to disk herniation and other types of disk disease. There are no cures for disk damage/degeneration. Both the hedgehog and Bmp signaling pathways have been implicated in the formation and postnatal maintenance of a number of tissues, however the tools necessary to investigate the function of these important signaling pathways in the intervertebral disks have not been available. In this proposal, we will use novel mouse stains and techniques we have recently developed to test our hypothesis that alterations in hedgehog and Bmp signaling pathways are responsible for age-related disk degeneration. In Aim 1, the role of hedgehog signaling in the development and maintenance of the intervertebral disks will be examined. Aim 2 will investigate the role a specific hedgehog family member, Shh, plays in the postembryonic maintenance of healthy intervertebral disks. In Aim 3, we propose to remove combinations of Bmp proteins, which function downstream of hedgehog signaling, from the intervertebral disks to investigate our hypothesis that inadequate stimulation of intervertebral disk cells by Bmp proteins results in disk degeneration. [unreadable] [unreadable] [unreadable]